Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates

ABSTRACT

Crystalline pantoprazole sodium Forms II, IV, V, VI, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX and XX; pantoprazole sodium solvates containing water, acetone, butanol, methylethylketone, dimethylcarbonate, propanol and 2-methylpropanol; and amorphous pantoprazole sodium are disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/434,445, filed on Dec. 19, 2002 and U.S.Provisional Patent Application Ser. No. 60/453,836, filed Mar. 12, 2003,the disclosures of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to the gastric acid secretion inhibitorpantoprazole in the solid state and, more particularly, to crystallineand amorphous forms of pantoprazole sodium having unique physicalproperties as well as processes for preparing them, pharmaceuticalcompositions containing them and methods of treating gastroesophagealreflux disease using them.

BACKGROUND OF THE INVENTION

Pantoprazole is a gastric acid secretion inhibitor. The systematicchemical name of pantoprazole is5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand its molecular structure is represented by formula (I).

U.S. Pat. No. 4,758,579 discloses that pantoprazole and many otherfluoroalkoxy substituted benzimidazoles are gastric acid secretioninhibitors. The '579 patent states that pantoprazole can be prepared byoxidation of the sulfide analog with meta-chloroperbenzoic acid byfollowing a procedure described in Example 2 of the '579 patent.According to Example 2, the oxidation is conducted in dichloromethane.The reaction mixture is quenched with sodium thiosulfate and sodiumcarbonate. The product is extracted from the aqueous phases withdichloromethane, washed with sodium thiosulfate, dried over magnesiumsulfate and concentrated. The residue is then crystallized fromdiisopropyl ether and recrystallized from a mixture of dichloromethaneand diisopropyl ether. Although pantoprazole sodium is the subject of aclaim in the '579 patent, a detailed procedure for convertingpantoprazole to its sodium salt is not set forth in the '579 patent.

Kohl, B. et al. J. Med. Chem. 1992, 35, 1049-57 reports a study of theinhibitor activity and pH dependent stability of a series ofdimethoxypyridyl-substituted methylsulfinylbenzimidazoles, includingpantoprazole. Pantoprazole sodium sesquihydrate was prepared by adding 6N NaOH to a solution of pantoprazole in a 6:1 ethanol:dichloromethanemixture at 20° C. After 10 minutes, diisopropyl ether was added untilthe mixture became turbid. After stirring for another two hours, theprecipitate was collected by filtration, washed with isopropyl ether anddried under vacuum at 40° C. The results of C, H, N and S analysis,coupled with the anticipated structure and molecular formula ofpantoprazole indicated that the product contained 6.5% water,corresponding to a sesquihydrate (1.5 mol./mol.) level of hydration.

International Publication No. WO 91/19710 discloses a monohydrate formof pantoprazole sodium. The monohydrate form obtained by following theteachings of the '710 publication crystallizes as small cubic crystals,has a melting point of 150-153° C. and dissolves with difficulty inacetone. According to the '710 publication, the sesquihydrate contains6.0-6.5% water and has a melting point of 137-140° C. The pantoprazolesodium monohydrate of the '710 publication can be made by dissolvingpantoprazole in acetone or another low ketone and adding sodiumhydroxide solution to the mixture. The monohydrate is obtainedimmediately in pure form after adding the sodium hydroxide solution.Alternatively, the monohydrate of the '710 publication can be obtainedby crystallization from a solution prepared by dissolving pantoprazolesodium sesquihydrate in acetone or other lower ketone.

Pantoprazole is the active ingredient of a pharmaceutical product thatis marketed in the United States by Wyeth-Ayerst Inc. under the brandname Protonix®. Protonix® is approved by the U.S. Food and DrugAdministration for short term treatment of erosive esophagitisassociated with gastroesophageal reflux disease (“GERD”), maintenance ofhealing of erosive esophagitis and pathological hypersecretoryconditions including Zollinger-Ellison syndrome. According to thepackage insert for Protonix®, the product contains a monosodium salt ofpantoprazole (hereafter “pantoprazole sodium”) in a sesquihydrate stateof hydration.

The present invention relates to the solid state physical properties ofpantoprazole sodium Solid state physical properties include, forexample, the flowability of the milled solid. Flowability affects theease with which the material is handled during processing into apharmaceutical product. When particles of the powdered compound do notflow past each other easily, a formulation specialist must take thatfact into account in developing a tablet or capsule formulation, whichmay necessitate the use of glidants such as colloidal silicon dioxide,talc, starch or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound isits rate of dissolution in aqueous fluid. The rate of dissolution of anactive ingredient in a patient's stomach fluid can have therapeuticconsequences since it imposes an upper limit on the rate at which anorally-administered active ingredient can reach the patient'sbloodstream The rate of dissolution is also a consideration informulating syrups, elixirs and other liquid medicaments. The solidstate form of a compound may also affect its behavior on compaction andits storage stability.

These practical physical characteristics are influenced by theconformation and orientation of molecules in the unit cell, whichdefines a particular polymorphic form of a substance. The polymorphicform may give rise to thermal behavior different from that of theamorphous material or another polymorphic form. Thermal behavior ismeasured in the laboratory by such techniques as capillary meltingpoint, thermogravimetric analysis (TGA) and differential scanningcalorimetry (DSC) and can be used to distinguish some polymorphic formsfrom others. A particular polymorphic form may also give rise todistinct spectroscopic properties that may be detectable by powder X-raycrystallography (“PXRD”), solid state ¹³C NMR spectrometry and infraredspectrometry.

These spectroscopic and utilitarian properties can be influenced bycontrolling the conditions under which a compound is obtained in solidform. There is a wide variety of techniques that have the potential ofproducing different crystalline forms of a compound. Examples includecrystallization, crystal digestion, sublimation and thermal treatment.However, none of these techniques can be expected a priori to produce anew solid state form of a compound.

The present invention also relates to solvates of pantoprazole sodium.When a substance crystallizes out of solution, it may trap molecules ofsolvent at regular intervals in the crystal lattice. Solvation alsoaffects utilitarian physical properties of the solid state likeflowability and dissolution rate.

The discovery of new polymorphic forms and solvates of apharmaceutically useful compound provides a new opportunity to improvethe performance characteristics of a pharmaceutical product. It enlargesthe repertoire of materials that a formulation scientist has availablefor designing, for example, a pharmaceutical dosage form of a drug witha targeted release profile or other desired characteristic. Newpolymorphic forms and solvates of pantoprazole have now been discovered.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides new crystalline forms ofpantoprazole sodium and amorphous pantoprazole sodium, solvates andhydrates thereof.

In one aspect, the present invention provides pantoprazole sodiumhydrates containing between about 7% to about 30% water (indicated by aLOD).

In another aspect, the present invention provides pantoprazole sodiumForm II, characterized by a PXRD pattern having peaks at 16.6, 16.9,17.5, 21.3, 21.7 and 22.2±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumacetone solvate.

In another aspect, the present invention provides pantoprazole sodiumForm IV, which has produced a PXRD pattern having peaks at 5.5, 13.8,16.5, 17.0, 26.2 and 26.6±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumbutanol solvate.

In another aspect, the present invention provides pantoprazole sodiumForm V, which has produced a PXRD pattern having peaks at 5.8, 12.3,19.2, 19.7, 20.3 and 20.7±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumForm VI, characterized by a PXRD pattern having peaks at 17.9, 19.5,20.4, 21.4, 24.6±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiummethylethylketone solvate.

In another aspect, the present invention provides pantoprazole sodiumForm VIII, which has produced a PXRD pattern having peaks at 5.6, 12.1,13.0, 13.7±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumdimethylcarbonate solvate.

In another aspect, the present invention provides pantoprazole sodiumForm IX, which has produced a PXRD pattern having peaks at 5.3, 13.6,16.9, 17.3±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumpropanol solvate.

In another aspect, the present invention provides pantoprazole sodiumForm X, which has produced a PXRD pattern having peaks at 16.4, 18.3,19.0, 19.7, 21.9±0.2 degrees two-theta.

In another aspect, the present invention provides anhydrous pantoprazolesodium.

In another aspect, the present invention provides pantoprazole sodiumForm XI, characterized by a PXRD pattern having peaks at 6.0, 16.0,24.4, 25.1, 25.8±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodium2-methylpropanol solvate.

In another aspect, the present invention provides pantoprazole sodiumForm XII, which has produced a PXRD pattern having peaks at 5.6, 15.7,19.4, 24.7, 28.3±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumForm XIII, characterized by a PXRD pattern having peaks at 6.7, 15.9,23.6, 27.7, 29.3, 30.6±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumForm XIV, characterized by a PXRD pattern having peaks at 5.7, 17.0,18.1, 22.7 and 25.8±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumForm XV, characterized by a PXRD pattern having peaks at 20.7, 21.4,21.8 and 23.3±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumForm XVI, characterized by a PXRD pattern having peaks at 20.7, 21.4,21.8 and 23.3±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumhydrate-methylethylketone solvate.

In another aspect, the present invention provides pantoprazole sodiumForm XVII, which has produced a PXRD pattern having peaks at 15.2, 15.7,25.8, and 26.5±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumhydrate-acetone solvate.

In another aspect, the present invention provides pantoprazole sodiumForm XVIII, which has produced a PXRD pattern having peaks at 11.2,13.2, 13.5, 13.8, 14.1±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumdihydrate.

In another aspect, the present invention provides pantoprazole sodiumForm XIX, which has produced a PXRD pattern having peaks at 11.3, 13.4,13.8, 26.2 and 26.6±0.2 degrees two-theta.

In another aspect, the present invention provides pantoprazole sodiumtrihydrate.

In another aspect, the present invention provides pantoprazole sodiumForm XX, which has produced a PXRD pattern having peaks at 15.4, 17.9,24.6, 25.9, 26.2, and 26.5±0.2 degrees two-theta.

In another aspect, the present invention provides amorphous pantoprazolesodium.

Pantoprazole sodium monohydrate can be prepared by precipitation ofpantoprazole sodium from a solution in selected diluents wherein thesolution is prepared by add pantoprazole and sodium hydroxide to thediluent. In another process a heterogeneous mixture of pantoprazolesodium and either dimethylcarbonate or acetone and pantoprazole sodiumis separated from the heterogeneous mixture and recovered aspantoprazole sodium Form I.

Pantoprazole sodium sesquihydrate can be prepared by forming a solutionof pantoprazole and sodium hydroxide in a selected diluent andprecipitating crystals of the sesquihydrate from the solution. Inaddition, the sesquihydrate can be prepared by forming a heterogeneousmixture of pantoprazole sodium in a selected solvent and recovering thesesquihydrate from the mixture.

The present invention further provides processes for preparing knownpantoprazole sodium monohydrate and sesquihydrate.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representative PXRD pattern of pantoprazole sodium Form II.

FIG. 2 is a representative PXRD pattern of pantoprazole sodium Form IV.

FIG. 3 is a representative PXRD pattern of pantoprazole sodium Form V.

FIG. 4 is a representative PXRD pattern of pantoprazole sodium Form VI.

FIG. 5 is a representative PXRD pattern of pantoprazole sodium FormVIII.

FIG. 6 is a representative PXRD pattern of pantoprazole sodium Form IX.

FIG. 7 is a representative PXRD pattern of pantoprazole sodium Form X.

FIG. 8 is a representative PXRD pattern of pantoprazole sodium Form XI.

FIG. 9 is a representative PXRD pattern of pantoprazole sodium Form XII.

FIG. 10 is a representative PXRD pattern of pantoprazole sodium FormXIII.

FIG. 11 is a representative PXRD pattern of pantoprazole sodium FormXIV.

FIG. 12 is a representative PXRD pattern of pantoprazole sodium Form XV

FIG. 13 is a representative PXRD pattern of pantoprazole sodium FormXVI.

FIG. 14 is a representative PXRD pattern of pantoprazole sodium FormXVII.

FIG. 15 is a representative PXRD pattern of pantoprazole sodium FormXVIII.

FIG. 16 is a representative PXRD pattern of pantoprazole sodium FormXIX.

FIG. 17 is a representative PXRD pattern of pantoprazole sodium Form XX.

FIG. 18 is a representative PXRD pattern of amorphous pantoprazolesodium.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides seventeen novel crystalline solids ofpantoprazole sodium that have been denominated Forms II, IV, V, VI,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX andamorphous pantoprazole sodium. The novel forms of pantoprazole sodiumproduce unique PXRD patterns which can be used to identify anddistinguish each of the novel forms from each other and knownpantoprazole sodium Form I (monohydrate) and known pantoprazole sodiumsesquihydrate.

The PXRD patterns depicted in the accompanying figures were obtained ona Scintag X-Ray powder diffractometer model X'TRA with a copper tubesolid state detector. A round standard aluminum sample holder with roundzero background quartz plate was used. Scanning parameters: Range:2-40°2θ: continuous scan, Rate: 3 deg./min.

The present invention also provides acetone, butanol, methylethylketone,dimethylcarbonate, propanol and 2-methylpropanol solvates ofpantoprazole sodium.

The present invention also provides hydrates of pantoprazole sodiumcontaining between about 7% and about 30% water (as indicated by LOD).

The present invention also provides hydrate-methylethylketone solvateand hydrate-acetone solvate of pantoprazole sodium.

The present invention also provides anhydrous pantoprazole sodium.

The degree to which they are solvated was assessed by thermogravimetricanalysis (“TGA”). The loss on drying (“LOD”) of each of the solvatedforms was measured by TGA using A Mettler TG50: Sample weight: 7-15 mg,heating rate: 10° C./min. Standard Alumina crucibles were used. Watercontents were measured by Karl-Fisher titration method.

As used herein, the term “treating” refers to dissolving, granulating,slurrying or exposing to vapor.

Pantoprazole Sodium Form II

In a first aspect, the present invention provides a novel crystallinesolid form of pantoprazole sodium that has been denominated Form II.This form can also exist as a hydrate. The hydration level is indicatedby a LOD of 5-7% on heating from 25° C. to 170° C. and Karl Fisheranalysis.

Pantoprazole sodium Form II can be differentiated from other hydratedforms by its PXRD pattern, a representative example of which is providedin the diffractogram of FIG. 1. Particularly characteristic peaks in thePXRD pattern occur at 16.6, 16.9, 17.5, 21.3, 21.7 and 22.2±0.2 degreestwo-theta. Additional peaks occur at 111.6, 12.2, 13.1, 14.2, 14.8,20.6, 22.9 and 23.3±0.2 degrees two-theta.

Pantoprazole sodium Form II can be prepared by forming a solution ofpantoprazole and excess sodium hydroxide in acetone and crystallizingForm II from the solution. Preferably, pantoprazole is added as the freebase, though the sodium salt may be used. Excess sodium hydroxide isconveniently added as a concentrated aqueous NaOH solution. Sodiumhydroxide should be added in an amount of from about 1 to about 2 molarequivalents with respect to pantoprazole. In a particularly preferredprocedure, pantoprazole is dissolved in about 3-6 volumes of acetone.The solution is cooled to about 0° C. Then, the concentrated NaOHsolution is added. Crystallization of the novel form of pantoprazolesodium is substantially complete within about 1-5 hours. The crystalscan then be separated from the acetone by conventional means, such as byfiltering or decanting and they may be washed, preferably with acetone.

In this disclosure, sodium hydroxide is commonly used as a source ofsodium ions. However, it will be appreciated by those skilled in the artthat other sources of sodium ion may be substituted for sodiumhydroxide, such as sodium hydride, sodium methoxide, sodium ethoxide,sodium propoxide, sodium isopropoxide, sodium butoxide, sodiumisobutoxide and sodium t-butoxide and the like.

Pantoprazole Sodium Form IV

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium that can be obtained by contacting with acetoneunder certain controlled conditions. This crystalline solid has beendenominated Form IV.

Pantoprazole sodium Form IV can be identified by its PXRD pattern, arepresentative example of which is provided in the diffractogram of FIG.2. The acetone solvate is characterized by PXRD peaks at: 5.5, 13.8,16.5, 17.0, 26.2 and 26.6±0.2 degrees two-theta. Additional peaks occurat 10.1, 10.5, 11.3, 12.0, 13.4, 15.4, 17.6, 18.4, 19.6, 19.9, 23.0,23.5, 27.9±0.2 degrees two-theta.

Different samples of pantoprazole sodium Form IV have yielded differentdegrees of weight loss on heating. The most frequently observed loss isabout 11-12 weight % when the sample is heated to 115° C., though LODshave varied from 10-30%. Form IV also contains water.

Pantoprazole sodium Form IV can be prepared by treating pantoprazolesodium Form II in acetone followed by crystallization without drying orby other means of contacting pantoprazole sodium Form II with acetonewhich are effective to induce the solid state conversion of Form II toForm IV. Generally, such conditions include techniques that involveforming a heterogeneous mixture of the Form II crystals and acetone.Such techniques include without limitation those known to the skilledartisan as slurrying, suspending, granulating, triturating anddigesting. Hereafter, the formation of a heterogenous mixture of a solidand a liquid includes all of these techniques and does not limit theproportion of solid and liquid used in any way. In addition, Form IV canbe prepared by contact of Form II with acetone vapors. Accordingly, asused in this disclosure the formation of a heterogeneous mixture alsoincludes solid:gas mixtures. The existence of a solid:gas mixture iseasily ascertained by those in the art since the gas is confined and influid communication with the crystals. Confinement and fluidcommunication may occur in a single vessel, but a single vessel is notstrictly necessary since multiple containers that hold the crystals andthe gas may be connected by pipes.

A particularly preferred process for preparing Form IV, wherein aheterogenous mixture of pantoprazole sodium Form II with acetone,preferably in a ratio of 1:10 (w/w) or greater, is agitated at roomtemperature for 8-12 h (e.g. overnight), is effective in convertingsubstantially all of the Form II crystals to Form IV. Although a greaterproportion of acetone may be used, the yield of crystals is likely tosuffer unless steps are taken to drive dissolved pantoprazole out ofsolution such as cooling or adding an antisolvent in which pantoprazolesodium is insoluble or only sparingly soluble.

Pantoprazole sodium Form IV also is accessible starting with amorphouspantoprazole sodium (described below) using generally the sametechniques used to convert Form II to Form IV. In particular, Form IVmay be prepared by forming a heterogeneous mixture of amorphouspantoprazole sodium in acetone, and maintaining contact preferably for30 minutes or more and then separating the solid from acetone, such asby filtering or decanting. The conversion of the amorphous form intoForm IV is easily followed because the conversion of the amorphouspowder to fine crystals can be observed with the naked eye. A preferredacetone:solid ratio for the process is 2:1 or less (resulting in amixture commonly known as a slurry). A greater solvent:solid ratio (e.g.4:1) tends to result in a lower low yield without an offsettingadvantage such as acceleration of the conversion. The obtained crystalsmay be optionally dried gently at a temperature of up to 60° C., morepreferably up to 40° C., for about 0-1 h, more preferably up to 30 min.However, drying at significantly higher temperature or for aconsiderably longer time may cause desolvation of the Form IV crystalsinto monohydrate crystals.

Pantoprazole Sodium Acetone Solvate

Another aspect of this invention is crystalline pantoprazole sodiumacetone solvate.

Pantoprazole sodium acetone solvate can be prepared by treatingpantoprazole sodium Form II with acetone followed by crystallizationwithout drying or by other means of contacting pantoprazole sodium FormII with acetone which are effective to induce the solid state conversionof Form II to an acetone solvate.

In addition, an acetone solvate can be prepared by contact of Form IIwith acetone vapors.

In a particularly preferred process for preparing an acetone solvate, aheterogenous mixture of pantoprazole sodium Form II and acetone,preferably in a Form II:acetone ratio of 1:10 (w/w) or greater, isagitated at room temperature for 8-12 h. These conditions are generallyeffective in converting substantially all of the Form II crystals to anacetone solvate.

Pantoprazole sodium acetone solvate also is accessible starting withamorphous pantoprazole sodium (described below) using generally the sametechniques used to convert Form II to an acetone solvate.

Pantoprazole Sodium Form V

Another aspect of the present invention is a novel crystalline solid ofpantoprazole sodium that can be obtained by contacting with 1-butanolunder certain controlled conditions. This crystalline solid has beendenominated Form V.

Pantoprazole sodium Form V can be identified by its PXRD pattern, arepresentative example of which is provided in the diffractogram of FIG.3. The 1-butanol solvate is characterized by PXRD peaks at 5.8, 12.3,19.2, 19.7, 20.3 and 20.7±0.2 degrees two-theta. Additional peaks occurat: 13.3, 14.0, 16.0, 17.1, 18.6, 22.8, 24.3, 25.3, 25.8±0.2 degreestwo-theta.

Samples of pantoprazole sodium Form V lose about 8-30% of their weightwhen heated up to 160° C. Typically they lose about 10 to 12% of theirweight when heated to 160° C. Karl Fisher analysis shows that this1-butanol solvate can contain about 15% water.

Pantoprazole sodium is appreciably soluble in 1-butanol. Accordingly,initial investigation focused on how this solvate could be produced bycrystallization from a solution rather than a heterogeneous technique.We discovered that combining free pantoprazole and solid sodiumhydroxide in 1-butanol and crystallization of the resulting pantoprazolesodium salt yielded Form V. The presence of minor amounts of wateroriginating from the use of non-anhydrous 1-butanol, a hydrated startingmaterial or water adsorbed on the equipment used for crystallization hasno effect on the crystal form obtained.

In addition, we discovered that Form V can be prepared by exposingcrystals of pantoprazole sodium Form II, to 1-butanol vapors at roomtemperature. The conversion can be effected in a few of weeks, thoughmore elevated temperatures may accelerate the conversion.

The obtained Form V crystals may be optionally dried gently at atemperature of up to 60° C., more preferably up to 40° C., for about 0-1h, more preferably up to 30 min. More vigorous drying at highertemperature or more time, tends to cause the transformation of Form Vcrystals into Form XIII crystals.

Pantoprazole Sodium Butanol Solvate

Another aspect of the present invention is crystalline pantoprazolesodium butanol solvate. Pantoprazole sodium butanol solvate is obtainedby combining free pantoprazole and solid sodium hydroxide in 1-butanoland crystallizing the resulting pantoprazole sodium salt. In addition,we discovered that a butanol solvate can be prepared by exposingcrystals of pantoprazole sodium Form II, to 1-butanol vapors at roomtemperature.

Pantoprazole Sodium Form VI

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium that can be obtained by contacting with water undercertain controlled conditions. This crystalline solid has beendenominated Form VI. This form can also exist as a hydrate.

Pantoprazole sodium Form VI is identifiable by its PXRD pattern, arepresentative example of which is depicted in FIG. 4. Form VI ischaracterized by PXRD peaks at 17.9, 19.5, 20.4, 21.4, 24.6±0.2 degreestwo-theta. Additional peaks occur at 6.3, 10.1, 15.5, 20.7, 23.0, 26.3,29.4 and 29.9±0.2 degrees two-theta.

Pantoprazole sodium Form VI loses about 10-30% of its weight on heatingto 150° C. A weight loss of 10-12% is considered the minimum weight lossto be expected for this form of pantoprazole sodium.

Pantoprazole sodium Form VI can be prepared by crystallizingpantoprazole sodium from a mixture of methanol and water. The followingis a preferred procedure. Pantoprazole sodium is dissolved in a minimumamount of a methanol and water mixture, preferably about a 1:1 mixture.The solution is left exposed to the atmosphere allowing solvent toevaporate, while inducing slow crystallization of pantoprazole sodium.The mixture is conveniently left in an open flask overnight. The periodof time needed for crystals of Form VI to form depends on the ratio ofMeOH to water. More solvent must be evaporated, requiring more time, asthe proportion of methanol is increased. A ratio of 1:1 methanol:watermixture is preferred because crystals usually form upon standingovernight.

Pantoprazole sodium Form VI also can be prepared by exposingpantoprazole sodium Form II to water vapors, preferably at roomtemperature, for a period of time sufficient to effect the conversion.The conversion of Form II into Form VI typically requires a period of1-3 weeks at room temperature.

The Form VI crystals may be optionally dried gently at a temperature ofup to 50° C., preferably 40° C. or less, for about 0-1 h, morepreferably up to 30 min. More vigorous drying of Form VI samples athigher temperature and for longer periods of time, tends to result in aloss of crystallinity resulting in an amorphous material. Over-drying ofForm VI crystals also may result in a mixture of Form I and amorphousform.

Pantoprazole Sodium Form VIII

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium that can be obtained by contacting withmethylethylketone (“MEK”) under certain controlled conditions. Thispolymorph or pseudopolymorph has been denominated Form VIII.

Form VIII can be identified by its PXRD pattern, a representativeexample of which is provided in the diffractogram of FIG. 5. Form VIIIis characterized by PXRD peaks at 5.6, 12.1, 13.0, 13.7±0.2 degreestwo-theta. Additional peaks appear at 15.8, 16.1, 16.8, 17.1, 19.4,20.0, 20.5, 22.6, 24.1, 24.5, 25.2, 25.5, 27.2±0.2 degrees two-theta.

Samples of Form VIII typically lose 16-18% of their weight upon heatingto 125° C. Karl Fisher analysis shows that Form VIII contains 5-6 wt. %water.

Pantoprazole sodium Form VIII can be prepared by dissolving pantoprazolesodium Form II in MEK followed by crystallization without drying or byforming a heterogeneous mixture of pantoprazole sodium (in any solvationstate or polymorphic form) and MEK and maintaining the mixture for aperiod of time sufficient to convert the crystals to Form VIII.

The obtained crystals may be optionally dried gently at a temperature ofup to 50° C., more preferably up to 40° C., for about 0-1 h, morepreferably up to 30 min. More vigorous drying of Form VIII at highertemperature or for a longer period of time, may cause a transformationinto Form I monohydrate.

Pantoprazole Sodium Methylethylketone Solvate

Another aspect of this invention is crystalline pantoprazole sodiummethylethylketone solvate.

Pantoprazole sodium Form VIII can be prepared by dissolving pantoprazolesodium Form II in MEK followed by crystallization without drying or byforming a heterogeneous mixture of pantoprazole sodium (in any solvationstate or polymorphic form) and MEK and maintaining the mixture for aperiod of time sufficient to convert the crystals to Form VIII.

Pantoprazole Sodium Form IX

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium that can be obtained by contacting withdimethylcarbonate under certain controlled conditions. This crystallinesolid has been denominated Form IX.

Pantoprazole sodium Form IX can be identified by its PXRD pattern, arepresentative example of which is provided in the diffractogram of FIG.6. Form IX is characterized by PXRD peaks at 5.3, 13.6, 16.9, 17.3±0.2degrees two-theta. Additional peaks appear at 10.6, 11.2, 18.5, 19.3,19.9, 21.2, 22.8, 26.1, 26.7±0.2 degrees two-theta.

Typical samples of Form IX lose 14-20% of their weight on heating to160° C. Karl Fisher analysis of Form IX shows that it contains about 9wt. % water.

Form IX can be prepared by forming a heterogeneous mixture ofpantoprazole sodium (in any solid state form) and dimethylcarbonate andmaintaining the heterogeneous mixture for a period of time sufficient toeffect conversion and separating the crystals from thedimethylcarbonate. At room temperature, complete conversion typicallytakes from 8 to 12 h.

The obtained crystals may be optionally dried gently at a temperature ofup to 50° C., more preferably up to 40° C., for about 0-1 h, morepreferably up to 30 min. More vigorous drying of Form IX sample athigher temperature or for a longer period of time may cause atransformation into Form I monohydrate.

Pantoprazole Sodium dimethylcarbonate Solvate

Another aspect of this invention is crystalline pantoprazole sodiumdimethylcarbonate solvate.

The dimethylcarbonate solvate can be prepared by forming a heterogeneousmixture of pantoprazole sodium (in any solid state form) anddimethylcarbonate and maintaining the heterogeneous mixture for a periodof time sufficient to effect conversion and separating the crystals fromthe dimethylcarbonate.

Pantoprazole Sodium Form X

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium that can be obtained by contacting with 1-propanolunder certain controlled conditions. This crystalline solid has beendenominated Form X.

Pantoprazole sodium Form X can be identified by its PXRD pattern, arepresentative example of which is provided in the diffractogram of FIG.7. Form X is characterized by PXRD peaks at 16.4, 18.3, 19.0, 19.7,21.9±0.2 degrees two-theta. Additional peaks appear at 10.9, 11.3, 13.6,14.2, 15.5, 23.2, 24.7, 25.6, 25.8, 28.2±0.2 degrees two-theta.

Samples of Form X typically lose 11-13% of their weight on heating to125° C., which corresponds to the expected 11.3% weight loss expectedfor a 1:1 solvate of 1-propanol and pantoprazole sodium. Karl Fisheranalysis shows that Form X contains 5 to 7 wt. % water.

Due to the high solubility of pantoprazole sodium in 1-propanol, initialefforts at producing this form focused on crystallization processes.Again, conditions depleted of water, yet not rigorously anhydrous wereinvestigated. We discovered that Form X can be obtained bycrystallization from a solution formed by combining free pantoprazolewith sodium hydroxide in 1-propanol.

The obtained crystals may be optionally dried gently at a temperature ofup to 60 C, more preferably up to 40 C, for about 0-1 h, more preferablyup to 30 min. More vigorous drying of Form X sample may cause to atransformation into Form I monohydrate.

Pantoprazole Sodium Propanol Solvate

Another aspect of this invention is crystalline pantoprazole sodiumpropanol solvate. We discovered that a propanol solvate can be obtainedby crystallization from a solution formed by combining free pantoprazolewith sodium hydroxide in 1-propanol.

Pantoprazole Sodium Form XI

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium which has been denominated Form XI.

Form XI is identifiable by its PXRD pattern, a representative example ofwhich is provided in the differactogram of FIG. 8. Form XI ischaracterized by PXRD peaks at 6.0, 16.0, 24.4, 25.1, 25.8±0.2 degreestwo-theta. Additional peaks appear at 14.9, 16.7, 17.0, 18.2, 20.5,21.6, 23.2±0.2 degrees two-theta. Form XI it loses less than 1% of itsweight on heating up to 120° C., indicating that it is anhydrous.

Pantoprazole sodium Form XI may be prepared by forming a solution bycontacting a hydrate of pantoprazole sodium with methanol, drying thesolution with a drying agent, separating the drying agent andevaporating the methanol. In our experiments, the residue was notcrystalline and we had difficulty crystallizing pantoprazole sodium frommethanol and when successful we obtained a methanol solvate. The usuallyviscous oil residue can be converted to an anhydrous crystalline form ofpantoprazole sodium by forming a heterogeneous mixture of the residueand acetone (the acetone should contain less than 0.01% water).Preferably from about 1:5 to about 2:5 acetone:residue (v/w) should beused. The heterogeneous mixture is agitated for a period of time forsubstantially all of the oily residue to become a crystalline solid. Theconversion typically takes about 2-6 hours at room temperature.

Anhydrous Pantoprazole Sodium

Another aspect of this invention is crystalline anhydrous pantoprazolesodium. Anhydrous Pantoprazole sodium may be prepared by forming asolution by contacting a hydrate of pantoprazole sodium with methanol,drying the solution with a drying agent, separating the drying agent andevaporating the methanol. In our experiments, the residue was notcrystalline and we had difficulty crystallizing pantoprazole sodium frommethanol and when successful we obtained a methanol solvate. The usuallyviscous oil residue can be converted to an anhydrous crystalline form ofpantoprazole sodium by forming a heterogeneous mixture of the residueand acetone (the acetone should contain less than 0.01% water).Preferably from about 1:5 to about 2:5 acetone:residue (v/w) should beused. The heterogeneous mixture is agitated for a period of time forsubstantially all of the oily residue to become a crystalline solid. Theconversion typically takes about 2-6 hours at room temperature.

Pantoprazole Sodium Form XI

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium that can be obtained by contacting with 2-methylpropanol under certain controlled conditions. This crystalline solid hasbeen denominated Form XII.

Form XII is identifiable by its PXRD pattern, a representative exampleof which is depicted in FIG. 9. Form XII is characterized by PXRD peaksat 5.6, 15.7, 19.4, 24.7, 28.3±0.2 degrees two-theta. Additional peaksappear at 11.1, 13.6, 16.0, 18.4, 19.4, 20.9, 22.2, 23.0, 25.3, 25.8±0.2degrees two-theta.

Samples of Form XII lose about 15-20% of their weight on heating from 70to 150° C. Karl Fisher analysis shows that Form XII contains 3-4 wt. %water

Pantoprazole sodium Form XII can be prepared by forming a solution ofpantoprazole sodium in 2-methyl propanol and then precipitating crystalsof pantoprazole sodium from the solution. Preferably, the pantoprazolesodium is dissolved in a minimum amount of 2-methylpropanol at refluxtemperature. Once a clear solution is obtained, heating may be ceasedand crystals of pantoprazole sodium 2-methylpropanol solvate willprecipitate from the solution if allowed to stand for a sufficientamount of time at room temperature, typically 10-20 h.

The obtained crystals may be optionally dried gently at a temperature ofup to 60° C., more preferably up to 40° C., for about 0-1 h, morepreferably for 30 min. or less. More vigorous drying at highertemperature or for a longer period of time, may cause the transformationof Form XII crystals into form XIII crystals. In some cases, morevigorous drying may result in a loss of crystallinity leading toamorphous material or mixtures of amorphous and crystalline material.

Pantoprazole Sodium 2-Methylpropanol Solvate

Another aspect of this invention is crystalline pantoprazole sodium2-methylpropanol solvate. Pantoprazole sodium 2-methylpropanol solvatecan be prepared by forming a solution of pantoprazole sodium in2-methylpropanol and then precipitating crystals of pantoprazole sodiumfrom the solution.

Pantoprazole Sodium Form XIII

Another aspect of this invention is a crystalline solid of pantoprazolesodium, which has been denominated form XIII. This for can also exist asa hydrate.

Pantoprazole sodium Form XIII is identifiable by its PXRD pattern, arepresentative example of which is provided as FIG. 10. Form XIII ischaracterized by PXRD peaks at: 6.7, 15.9, 23.6, 27.7, 29.3, 30.6±0.2degrees two-theta. Additional peaks appear at 13.4, 13.9, 17.1, 19.2,20.4, 21.0, 25.9±0.2 degrees two-theta.

Samples of Form XIII lose from 7 to 10% upon heating to 150° C.

Pantoprazole sodium Form XIII can be prepared by forming a solution ofpantoprazole sodium in a diluent selected from the group consisting oflower ketone solvents that are liquid at room temperature, such asacetone and methyl ethyl ketone (“MEK”) and 2-propanol, crystallizingpantoprazole sodium Form XIII from the solution and separating thecrystals from the diluent. Pantoprazole sodium is preferably dissolvedin a minimum amount of the diluent at reflux temperature. Upon cessationof heating, crystals should begin to precipitate from a solution inacetone within about an hour, typically within about 15 minutes. WhenMEK is used, the mixture should be allowed to stand for 10-20 h becausecrystallization is slower.

Pantoprazole sodium Form XIII is also accessible by solid state thermalconversion. We have discovered that when pantoprazole sodium Form V isheated to temperatures above the recommended drying temperature for thatsolvate, the crystal structure will convert into the Form XIII crystalstructure. Preferred conditions for conducting this conversion isheating to 50-80° C., more preferably 60-70° C., for from 1-5 h, morepreferably 2-3 h.

Pantoprazole sodium Form XIII is also accessible by solid state thermalconversion of Form XII. The conditions for converting Form XII to FormXIII are generally similar to the conditions used when starting fromForm V. In particular, Form XII is obtained by heating Form XII to50-80° C., preferably 60-70° C. for 1-5 hours, preferably 2-3 hours. Theobtained crystals may be optionally dried gently at a temperature of upto 60° C., more preferably up to 40° C., for about 0-1 h, morepreferably 30 min. or less. More vigorous drying may cause a loss ofcrystallinity resulting in an amorphous material.

Pantoprazole Sodium Form XIV

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium that can be obtained by contacting with 1-propanolunder certain controlled conditions. This crystalline solid has beendenominated Form XIV. This form can also exist as a hydrate.

Pantoprazole sodium Form XIV is identifiable by its PXRD pattern, arepresentative example of which is provided as FIG. 11. Form XIV ischaracterized by PXRD peaks at: 5.7, 17.0, 18.1, 22.7 and 25.8±0.2degrees two-theta. Additional peaks appear at 10.2, 10.9, 13.3, 14.1 and27.6±0.2 degrees two-theta.

Samples of Form XIV lose from 10-25% of their weight on heating to 170°C. Karl Fisher analysis shows that Form XIV contains between 2 and 6 wt.% water. Form XIV is therefore considered to contain 8-20 wt. %propanol.

Form XIV can be prepared by exposing pantoprazole sodium to vapors of1-propanol. They may be contacted by maintaining the pantoprazole sodiumunder 1-propanol vapor for a period of time sufficient to convert thestarting crystals to Form XIV. The solid:vapor phase conversion intoForm XIV is slow and can take as much as a month to complete.Alternatively, Form XIV can be produced by forming a solution ofpantoprazole sodium in 1-propanol, seeding the solution with Form XIVand precipitating dissolved pantoprazole from the solution as Form XIV.Crystallization typically takes 2-5 hours.

Pantoprazole Sodium Form XV

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium that can be obtained by thermal conversion ofpantoprazole sodium Form XIV. This crystalline solid has beendenominated Form XV. This form can also exist as a hydrate.

Pantoprazole sodium Form XV is identifiable by its PXRD pattern, arepresentative example of which is provided as FIG. 12. Form XV ischaracterized by PXRD peaks at: 20.7, 21.4, 21.8 and 23.3±0.2 degreestwo-theta. Additional peaks appear at 5.3, 11.6, 14.1, 14.8, 16.0 and19.0±0.2 degrees two-theta. Karl Fisher analysis shows that Form XIVcontains between 2 and 6 wt. % water.

Pantoprazole sodium Form XV can be produced from Form XIV. According tothis procedure, Form XIV is heated to from 30 to 100° C. for a period oftime sufficient to effect the conversion. Generally, Form XIVsubstantially completely converts to Form XV when kept overnight atabout 40-60° C. The conversion may be conducted at ambient pressures atthese temperatures. Conversion may be achievable at lower temperaturesunder reduced pressure. Progress of the conversion may be followed bymonitoring the reduction in intensity of Form XIV characteristic peaksat 5.7, 7.0, 18.2, 22.7 and 25.8±0.2 degrees two theta in the PXRDpattern of Form XIV and the appearance and increase in the intensity ofthe peak at 20.7, 21.4, 21.8 and 23.3±0.2 degrees two-theta in the PXRDpattern of Form XV.

Pantoprazole Sodium Form XVI

Another aspect of this invention is a crystalline solid of pantoprazolesodium that can be obtained by contacting with toluene under certaincontrolled conditions. This crystalline solid has been denominated FormXVI. This form can also exist as a hydrate.

Pantoprazole sodium Form XVI is identifiable by its PXRD pattern, arepresentative example of which is provided as FIG. 13. Form XVI ischaracterized by PXRD peaks at: 10.8, 11.4, 12.1 and 22.4±0.2 degreestwo-theta. Additional peaks appear at 5.5, 17.4, 24.3, 24.8±0.2 degreestwo-theta. Samples of Form XVI lose from 5-20% of their weight onheating to 170° C.

Pantoprazole sodium hydrate Form XVI can be produced by forming asolution of pantoprazole sodium in toluene diluent and precipitatingcrystals of pantoprazole sodium from the solution and separating thediluent. The procedure is further illustrated in Example 26.

Pantoprazole Sodium Form XVII

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium which has been denominated Form XVII. Form XVIIcontains about 5-6 wt. % water according to Karl Fischer analysis andloses 18-22 wt. % of its mass upon heating from 25° C. to 160° C.,indicating that it can contain from about 12 wt. % to about 17 wt. %methyl ethyl ketone.

Form XVII is identifiable by its PXRD pattern, a representative exampleof which is depicted in FIG. 14. Form XVII is characterized by a PXRDpattern having peaks at 15.2, 15.7, 25.8, and 26.5±0.2 degreestwo-theta.

Pantoprazole sodium Form XVII can be prepared by forming and thensufficiently agitating a heterogeneous mixture of pantoprazole sodium(in any solid state form) in methyl ethyl ketone for a period of timesufficient to effect the conversion to Form XVII. The production of FormXVII after twenty four hours indicates that the heterogeneous mixturewas sufficiently agitated to produce this crystalline form. However, theproduction of Form VIII is an indicator that the heterogeneous mixturewas not sufficiently agitated and steps to increase the agitation, suchas increasing a rate of stirring should be undertaken starting with newstarting material. Such routine adjustment in the operating conditionsis considered well within the ordinary skill in the art. Generallyspeaking, when working a typical laboratory scales of a few grams,mechanical or magnetic stirring of the heterogeneous mixture at 700 rpmor more should yield Form XVII. The temperature at which theheterogeneous mixture is maintained while being agitated is not criticalto successful practice of the invention, though it has been convenientto work at temperatures in the range of 20-35° C., yet more preferablyin the range of 25° C. to 30° C. A specific procedure for producing FormXVII is illustrated with Example 27, below.

Pantoprazole Sodium Hydrate-Methylethylketone Solvate

Another aspect of this invention is crystalline pantoprazole sodiumhydrate-methylethylketone solvate. Pantoprazole sodiumhydrate-methylethylketone solvate can be prepared by forming and thensufficiently agitating a heterogeneous mixture of pantoprazole sodium(in any solid state form) in methyl ethyl ketone for a period of timesufficient to effect the conversion to Form XVII.

Pantoprazole Sodium Form XVIII

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium which has been denominated Form XVIII. It containsabout 4-5 wt. % water according to Karl Fischer analysis and loses 10-11wt. % of its mass upon heating from 25° C. to 160° C., indicating thatit can contain from about 5 wt. % to about 7 wt. % acetone.

Form XVIII is identifiable by its PXRD pattern, a representative exampleof which is depicted in FIG. 15. Form XVIII is characterized by a PXRDpattern having peaks at 11.2, 13.2, 13.5, 13.8, 14.1±0.2 degreestwo-theta.

Pantoprazole sodium Form XVIII can be prepared by forming aheterogeneous mixture of pantoprazole sodium (in any solid state form)in acetone and then separating the acetone from the crystals. Theconversion takes from about 15 minutes to about 2 hours at roomtemperature. An illustrative procedure for preparing Form XVIII isprovided in Example 28 below.

Pantoprazole Sodium Hydrate-Acetone Solvate

Another aspect of this invention is crystalline pantoprazole sodiumhydrate-acetone solvate. Pantoprazole sodium hydrate-acetone solvate canbe prepared by forming a heterogeneous mixture of pantoprazole sodium(in any solid state form) in acetone and then separating the acetonefrom the crystals.

Pantoprazole Sodium Form XIX

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium which has been denominated Form XIX. It containsabout 6-9 wt. % water according to Karl Fischer analysis and loses thesame amount of its mass upon heating from 25° C. to 170° C., indicatingthat it contains little of any other solvent within its crystalstructure.

Form XIX is identifiable by its PXRD pattern, a representative exampleof which is depicted in FIG. 16. Form XIX is characterized by a PXRDpattern having peaks at 11.3, 13.4, 13.8, 26.2 and 26.6±0.2 degreestwo-theta.

Pantoprazole sodium Form XIX can be prepared by forming a homogeneousmixture of pantoprazole sodium (in any solid state form) in water underambient, elevated or vacuum conditions and then drying the residue.Preferred drying conditions 50° C. at ambient pressure.

Pantoprazole Sodium Dihydrate

Another aspect of this invention is pantoprazole sodium dihydrate.Pantoprazole sodium dihydrate can be prepared by forming a homogeneousmixture of pantoprazole sodium (in any solid state form) in water underambient, elevated or vacuum conditions and then drying the residue.

Pantoprazole Sodium Form XX

Another aspect of this invention is a novel crystalline solid ofpantoprazole sodium which has been denominated Form XX. It containsabout 11-12 wt. % water according to Karl Fischer analysis.

Form XX is identifiable by its PXRD pattern, a representative example ofwhich is depicted in FIG. 17. Form XX is characterized by a PXRD patternhaving peaks at 15.4, 17.9, 24.6, 25.9, 26.2, and 26.5±0.2 degreestwo-theta.

Pantoprazole sodium Form XX can be prepared by forming a heterogeneousmixture of pantoprazole sodium (in any solid state form) in moisthydrocarbons. The hydrocarbon component of the liquid phase of themixture is selected from any liquid aromatic hydrocarbon or any liquidaliphatic hydrocarbon in which water is soluble is soluble to the extentof at least one percent. There may be mentioned from among the suitablearomatic hydrocarbons, toluene, o-, — and p-xylenes and mixtures thereofas well as other alkyl substituted benzenes having substituents of 1-6aliphatic carbon atoms. Preferred aliphatic hydrocarbons contain fromfive to twelve carbon atoms, with reagent grade mixtures of hexanes,n-hexane and n-heptane being most preferred.

In accordance with the process for preparing pantoprazole sodium FormXX, the hydrocarbon component of the liquid phase is contacted with atleast enough water to produce a liquid phase containing from about 1 wt.% to about 10 wt. % water, more preferably about 1 wt. % to about 5 wt.% water. Depending upon the hydrocarbon, excess water may be used sothat saturation of the hydrocarbon results in the formation of a 1-10wt. % mixture. Excess water can then be separated by from the liquidphase by conventional means such as a separatory funnel.

The starting pantoprazole sodium is contacted with the liquid phase toform a heterogeneous mixture that is maintained under conditionseffective to convert it into Form XX. Stirring the mixture at roomtemperature for about 5 days is generally sufficient to complete theconversion.

After separating the liquid phase from the crystals, Form XX can bedried under mild conditions such as 50° C. at 10 mm Hg vacuum withoutcausing significant dehydration.

Illustrative procedures for preparing pantoprazole sodium Form XX areprovided in Examples 30-33, below.

Pantoprazole Sodium Trihydrate

Another aspect of this invention is crystalline pantoprazole sodiumtrihydrate. Pantoprazole sodium trihydrate can be prepared by forming aheterogeneous mixture of pantoprazole sodium (in any solid state form)in moist hydrocarbons. The hydrocarbon component of the liquid phase ofthe mixture is selected from any liquid aromatic hydrocarbon or anyliquid aliphatic hydrocarbon in which water is soluble is soluble to theextent of at least one percent. There may be mentioned from among thesuitable aromatic hydrocarbons, toluene, o-, C and p-xylenes andmixtures thereof as well as other alkyl substituted benzenes havingsubstituents of 1-6 aliphatic carbon atoms.

For convenience, the characteristic PXRD peaks of the novel crystallinepolymorphs and solvates of the present invention are set forth in Table1.

TABLE I Crystal Form Unique PXRD Peak Combinations (degrees two-theta)II 16.6, 16.9, 17., 21.3, 21. 722.2 IV 5.5, 13.8, 16.5, 17.0, 26.2, 26.6V 5.8, 12.3, 19.2, 19.7, 20.3, 20.7 VI 17.9, 19.5, 20.4, 21.4, 24.6 VIII5.6, 12.1, 13.0, 13.7 IX 5.3, 13.6, 16.9, 17.3 X 16.4, 18.3, 19.0, 19.7,21.9 XI 6.0, 16.0, 24.4, 25.1, 25.8 XII 5.6, 15.7, 19.4, 24.7, 28.3 XIII6.7, 15.9, 23.6, 27.7, 29.3, 30.6 XIV 5.7, 17.0, 18.1, 22.7, 25.8 XV20.7, 21.4, 21.8, 23.3 XVI 10.8, 11.4, 12.1, 22.4 XVII 15.2, 15.7, 25.8,26.5 XVIII 11.2, 13.2, 13.5, 13.8, 14.1 XIX 11.3, 13.4, 13.8, 26.2, 26.6XX 15.4, 17.9, 24.6, 25.9, 26.2, 26.5

Amorphous Pantoprazole Sodium

Another aspect of this invention is novel amorphous pantoprazole sodium,which produces a featureless PXRD pattern, as shown in FIG. 18.

Various processes that can be used to prepare amorphous pantoprazolesodium have already been mentioned in this disclosure. It may beprepared by excessive heating of pantoprazole sodium Forms V and XII,which leads to amorphous material via the intermediate polymorph FormXIII. When starting with Form XIII, preferred heating conditions arefrom 50 to 80° C., more preferably from 60 to 70° C. Completedestruction of crystallinity is usually complete in 2-5 h under theseconditions. Heating pantoprazole sodium Form VI under these conditionsalso yields amorphous material.

Amorphous pantoprazole sodium also is accessible by dissolvingcrystalline pantoprazole sodium or any solvate thereof in a C₁-C₄ loweralcohol, then evaporating the alcohol to leave a semi-solid or liquidresidue, forming a heterogeneous mixture of the residue and any solventin which pantoprazole sodium is not appreciably soluble and maintainingthe heterogeneous mixture until the residue solidifies, which typicallytakes 1 to 3 hours at room temperature.

Amorphous pantoprazole sodium also is accessible by precipitation ofpantoprazole sodium from a solution of pantoprazole sodium inacetonitrile. Preferably, the pantoprazole sodium is dissolved in aminimum amount of acetonitrile and precipitation is induced by addingany liquid in which pantoprazole sodium is not appreciably soluble.Precipitation is usually complete within about 24 hours.

Amorphous pantoprazole sodium also is accessible by precipitation from asolution in toluene. The solution is prepared by dissolving pantoprazolefree base and sodium hydroxide in the toluene. The sodium hydroxide ispreferably added to the toluene as a concentrated aqueous solution, mostpreferably about a 47% aqueous solution. After precipitation, theamorphous pantoprazole precipitate is separated from the toluene afterwhich it may be conventionally dried. Suitable drying conditions include45° C. under 10 mm Hg vacuum.

Amorphous pantoprazole sodium also can be prepared by heating any formof pantoprazole sesquihydrate to 100° C. or higher temperature.

We have also discovered new processes for preparing known pantoprazolesodium hydrates.

Processes for Preparing Pantoprazole Sodium Monohydrate

Pantoprazole sodium monohydrate may be prepared by forming a solution ofpantoprazole and sodium hydroxide in a diluent selected from the groupconsisting of tetrahydrofuran, methanol, 2-propanol, butanol,dimethylcarbonate, acetone, acetonitrile, and 1-propanol, precipitatingcrystals of pantoprazole sodium monohydrate from the solution, andseparating the crystals from the diluent. The starting material may bepantoprazole sodium or any solvate of it. Alternatively, the solutionmay be formed by separately adding free pantoprazole and sodiumhydroxide. Sodium hydroxide may be conveniently added separately as asolid or aqueous sodium hydroxide. Regardless of the method by whichpantoprazole and sodium hydroxide are contacted with the diluent, theamounts of starting material and diluent used are preferably such as toyield a concentration corresponding to about 0.2 to 1 g of pantoprazolesodium per milliliter of diluent.

Depending upon the concentration and choice of diluent, it may benecessary to heat the mixture to reflux to obtain a clear solution. Whenthe solution is refluxed, crystallization may be induced by cessation ofheating and allowing the mixture to return to room temperature.Crystallization may also be induced by adding an anti-solvent to themixture. Preferred anti-solvents are MTBE, toluene and cyclohexane.Particularly preferred diluent/anti-solvent combinations are furtherillustrated with Examples.

Pantoprazole sodium monohydrate may be prepared by forming aheterogeneous mixture by contacting pantoprazole sodium and a diluentselected from the group consisting of dimethylcarbonate and acetone, andrecovering pantoprazole sodium monohydrate Form I from the heterogeneousmixture. Preferred starting materials for the heterogeneous process arepantoprazole sodium monohydrate Form II, amorphous pantoprazole sodiumand pantoprazole sodium sesquihydrate.

Processes for Preparing Known Pantoprazole Sodium Sesquihydrate

Pantoprazole sodium Sesquihydrate can be prepared by forming a solutionof pantoprazole and sodium hydroxide in a diluent selected from thegroup consisting of 2-propanol, tetrahydrofuran, acetonitrile, methanol,ethanol, water, mixtures of sec-butanol and dichloromethane, and ethylacetate, precipitating crystals of pantoprazole sodium sesquihydratefrom the solution, and separating the crystals from the diluent. Thestarting material may be pantoprazole sodium or any solvate of it.Alternatively, the solution may be formed by separately adding freepantoprazole and sodium hydroxide. Sodium hydroxide may be convenientlyadded separately as solid or aqueous sodium hydroxide. Regardless of themethod by which pantoprazole and sodium hydroxide are contacted with thediluent, the amounts of starting material and diluent used arepreferably such as to yield a concentration corresponding to about 0.5to 1 g of pantoprazole sodium per milliliter of diluent.

Depending upon the concentration and choice of diluent, it may benecessary to heat the mixture to reflux to obtain a clear solution. Whenthe solution is refluxed, crystallization may be induced by cessation ofheating and allowing the mixture to return to room temperature.Crystallization may also be induced by adding an anti-solvent to themixture. Preferred anti-solvents are MTBE and heptane.

When the diluent is methanol or ethanol, the starting materials arepreferably free pantoprazole and solid sodium hydroxide.

Pantoprazole sodium sesquihydrate also can be prepared by forming aheterogeneous mixture by contacting pantoprazole sodium and a diluentselected from the group consisting of ethyl acetate, dichloromethane,water, dimethylcarbonate and 2-propanol, and recovering pantoprazolesodium sesquihydrate from the heterogeneous mixture. The amount ofpantoprazole used is preferably from about 0.1 g to 1 g per milliliterof diluent. Preferably, the diluents water and mixtures of water and2-propanol are used in a minor amount relative to the pantoprazolesodium on a weight basis. When the diluent is ethyl acetate,dichloromethane or dimethylcarbonate, it is preferably added in anamount equal or greater amount than the amount of pantoprazole sodium ona weight basis

Compositions and Dosage Forms of Crystalline And Amorphous PantoprazoleSodium

Pantoprazole sodium Forms II, IV, V, VI, VIII, IX, X, XI, XII, XIII,XIV, XV, XVI, XVII, XVIII, XIX, XX and amorphous pantoprazole sodium areuseful as the active ingredient in pharmaceutical compositions anddosage forms intended for administration of the gastric acid secretioninhibitor pantoprazole. Accordingly, these novel solid forms are usefulfor treating erosive esophagitis associated with GERD.

Pharmaceutical compositions of the present invention containpantoprazole sodium Form II, IV, V, VI, VIII, IX, X, XI, XII, XIII, XIV,XV, XVI, XVII, XVIII, XIX or XX, amorphous pantoprazole sodium ormixtures thereof with each other or with other forms of pantoprazolesodium. In addition to the active ingredient(s), the pharmaceuticalcompositions of the present invention can contain one or moreexcipients. Excipients are added to the composition for a variety ofpurposes.

Diluents increase the bulk of a solid pharmaceutical composition and canmake a pharmaceutical dosage form containing the composition easier forthe patient and care giver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. Avicel®),microfine cellulose, lactose, starch, pregelatinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage formlike a tablet can include excipients whose functions include helping tobind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions include forexample acacia, alginic acid, carbomer (e.g. carbopol),carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guargum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropylcellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g.Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin,methylcellulose, polymethacrylates, povidone (e.g. Kollidon®,Plasdone®), pregelatinized starch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach can be increased by the addition of a disintegrantto the composition. Disintegrants include for example alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants can be added to improve the flowability of non-compacted solidcomposition and improve the accuracy of dosing. Excipients that canfunction as glidants include for example colloidal silicon dioxide,magnesium trisilicate, powdered cellulose, starch, talc and tribasiccalcium phosphate.

When a dosage form such as a tablet is made by compaction of a powderedcomposition, the composition is subjected to pressure from punches and adie. Some excipients and active ingredients have a tendency to adhere tothe surfaces of the punches and die, which can cause the product to havepitting and other surface irregularities. A lubricant can be added tothe composition to reduce adhesion and ease release of the product formthe die. Lubricants include for example magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that can be included in the composition ofthe present invention include for example maltol, vanillin, ethylvanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaricacid.

Solid and liquid compositions can also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,pantoprazole sodium Forms II, IV, V, VI, VIII, IX, X, XI, XII, XIII,XIV, XV, XVI, XVII, XVIII, XIX or XX, amorphous pantoprazole sodium ormixtures thereof are suspended in a liquid carrier such as water,vegetable oil, alcohol, polyethylene glycol, propylene glycol orglycerin.

Liquid pharmaceutical compositions can contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that can be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention can alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include for example acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar can be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid can be added at levels safe for ingestion to improvestorage stability.

A liquid composition according to the present invention can also containa buffer such as guconic acid, lactic acid, citric acid or acetic acid,sodium guconate, sodium lactate, sodium citrate or sodium acetate.

Selection of excipients and the amounts to use can be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. Although the most suitable route in any given case willdepend on the nature and severity of the condition being treated, themost preferred route of the present invention is oral. The dosages canbe conveniently presented in unit dosage form and prepared by any of themethods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and losenges as well as liquid syrups,suspensions and elixirs.

A dosage form of the present invention is a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell can be madefrom gelatin and optionally contain a plasticizer such as glycerin andsorbitol, and an opacifying agent or colorant.

The active ingredient and excipients can be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filing can be prepared by wetgranulation. In wet granulation some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, which causes the powders to clumpup into granules. The granulate is screened and/or milled, dried andthen screened and/or milled to the desired particle size. The granulatecan then be tableted or other excipients can be added prior totableting, such as a glidant and/or a lubricant.

A tableting composition can be prepared conventionally by dry blending.For instance, the blended composition of the actives and excipients canbe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules can be compressed subsequently into atablet.

As an alternative to dry granulation, a blended composition can becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well-suited todirect compression tableting include microcrystalline cellulose, spraydried lactose, dicalcium phosphate dihydrate and colloidal silica. Theproper use of these and other excipients in direct compression tabletingis known to those in the art with experience and skill in particularformulation challenges of direct compression tableting.

A capsule filling of the present invention can comprise any of theaforementioned blends and granulates that were described with referenceto tableting, only they are not subjected to a final tableting step.

Capsules, tablets and lozenges and other unit dosage forms preferablycontain a dosage level of about 10 to about 100 mg of pantoprazolesodium Form I II, IV, V, VI, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI,XVII, XVIII, XIX or XX, amorphous pantoprazole sodium or mixturesthereof, more preferably about 45 mg. Other dosages may also beadministered depending on the need.

Having thus described the present invention with reference to certainpreferred embodiments, the invention will be further illustrated by theexamples which follow. These examples are provided for illustrativepurposes only and are not intended to limit the scope of the inventionin any way.

EXAMPLES

Pantoprazole and pantoprazole sodium were obtained from commercialsources. All organic solvents and reagents were used as received fromcommercial sources.

Preparation of Pantoprazole Sodium Form II Example 1

A 100 ml round bottomed flask equipped with a magnetic stir bar wascharged with acetone (50 ml). Pantoprazole (10 g, 25.7 mmol) was thenadded to the flask. After the pantoprazole had completely dissolved, thesolution was cooled to about 2° C. Forty seven percent sodium hydroxide(aq.) equivalent to 2.4 grams of solid sodium hydroxide (60.0 mmol) wasslowly added to the cooled solution. A precipitate began to formimmediately. The mixture was stirred for another two hours while theflask was allowed to warm to room temperature. The precipitate wasfiltered and washed with acetone (20 ml) and dried at 40° C. undervacuum to yield pantoprazole sodium Form II (6.9 g, 65%).

Preparation of Amorphous Pantoprazole Sodium Example 2

Pantoprazole sodium Form II (5.0 g) was dissolved at room temperature inabsolute ethanol (120 ml) in a flask equipped with a Soxlet extractorcontaining 30 g of 4 Å molecular sieves and a condenser mounted atop theSoxlet extractor. The solution was refluxed for 24 h with the condensedsolvent passing through the bed of molecular sieves and was returned tothe flask. Ethanol was removed by evaporation under vacuum, giving aresidue. The residue was triturated with MTBE (50.0 ml) for two hours.The solid was filtered and dried at 50° C. under 10 mm Hg vacuum toafford amorphous pantoprazole sodium.

Example 3

Pantoprazole sodium Form II (5.0 g) was dissolved in acetonitrile (25ml) at room temperature. MTBE (250 ml) was then slowly added. Thesolution was allowed to stand at room temperature for two days, givingthe crystallized product. The precipitate was filtered and dried at 65°C. for two hours under ambient pressure to afford a mixture ofpantoprazole sodium monohydrate and amorphous pantoprazole sodium.

Example 4

Pantoprazole sodium sesquihydrate was dried at 100° C. under 10 mmvacuum overnight, giving amorphous pantoprazole sodium.

Example 5

A 100 ml flask was charged with toluene (50.0 ml). Pantoprazole (5.0 g,12.8 mmol) and 47% aqueous NaOH (1.2 g) were added to the stirredsolvent at room temperature. The mixture was stirred until dissolutionand then overnight until precipitation. The solid was filtered givingpantoprazole sodium. The sample was dried at 45° C. under 10 mm Hgvacuum overnight, giving 4.21 g of amorphous pantoprazole sodium.

Preparation of Pantoprazole Sodium Acetone Solvate Form IV Example 6

Pantoprazole sodium Form II (5.0 g) in acetone (50 ml) was stirred atroom temperature for 24 h to give a pantoprazole sodium solvate withacetone that has been denominated pantoprazole sodium Form IV.

Example 7

Pantoprazole sodium Form II (2.0 g) and acetone (0.4 ml) were subjectedto rotary mixing in a rotary evaporator without vacuum at roomtemperature for two hours to afford pantoprazole sodium Form IV.

Example 8

Exposing pantoprazole sodium Form II (1.0 g) to acetone vapors in asealed vessel at room temperature for two weeks afforded pantoprazolesodium Form IV.

Example 9

Pantoprazole sodium Form II (5.0 g) was dissolved in acetone (50 ml) byheating at reflux. After cooling to room temperature the mixture wasstirred overnight. The crystals were filtered and analyzed by PXRD andTGA which showed that they were pantoprazole sodium Form IV. Drying ofForm IV at 50° C. under vacuum at 10 mm Hg vacuum overnight yieldedpantoprazole sodium Form I.

Example 10

Stirring amorphous pantoprazole sodium (1.6 g) in excess acetone (3.2ml) at room temperature for two hours and filtering to remove excessacetone afforded pantoprazole sodium Form IV.

Preparation of Pantoprazole Sodium 1-Butanol Solvate Form V Example 11

Pantoprazole (5.0 g, 12.8 mmol) and 98.5% NaOH (0.52 g, 12.8 mmol) weredissolved in 1-butanol (10.0 ml) at room temperature and the solutionwas stirred overnight at room temperature. The solution was cooled in arefrigerator and then stirred at room temperature until crystallizationoccurred. The crystals were filtered and dried at 50° C. under 10 mm Hgvacuum overnight to afford pantoprazole sodium Form V as determined byPXRD.

Example 12

Exposing pantoprazole sodium Form II (1.0 g) to 1-butanol vapors in asealed vessel at room temperature for two weeks also affordspantoprazole sodium Form V.

The procedure described in Example 34 also affords pantoprazole sodiumForm V.

Preparation of Pantoprazole Sodium Form VI Example 13

Exposing pantoprazole sodium Form II (1.0 g) to water vapors in a sealedvessel at room temperature for two weeks affords pantoprazole sodium innovel Form VI.

The procedure set out in Example 35 also affords pantoprazole sodiumForm VI.

Preparation of Pantoprazole Sodium Methyl Ethyl Ketone Solvate Form VIIIExample 14

Pantoprazole sodium monohydrate Form II (5.0 g) was slurried in MEK (50ml) at room temperature for 24 h. The crystals were filtered andanalyzed by PXRD and TGA which showed that they were a methyl ethylketone solvate that has been denominated Form VIII.

Example 15

Pantoprazole sodium Form II (1.0 g) and MEK (0.4 ml) were subjected torotary mixing in a rotary evaporator without vacuum at room temperaturefor two hours to afford pantoprazole sodium Form VIII.

Example 16

Pantoprazole sodium Form II (5.0 g) was dissolved in MEK (50 ml) byheating at reflux. After cooling to room temperature the mixture wasstirred overnight. The crystals were filtered and analyzed by PXRD andTGA which showed that they were a MEK solvate. Drying the crystals at50° C. under vacuum at 10 mm Hg vacuum yielded pantoprazole sodium FormI.

Preparation of Pantoprazole Sodium Dimethylcarbonate Solvate Form IXExample 17

Pantoprazole sodium Form II (5.0 g) was slurried with dimethylcarbonate(50 ml) at room temperature for 24 h. The crystals were filtered andanalyzed by PXRD and TGA which showed that they were a pantoprazolesodium solvate with dimethylcarbonate which has been denominated FormIX.

Preparation of Pantoprazole Sodium Solvate with 1-Propanol Form XExample 18

Pantoprazole (5.0 g, 12.8 mmol) and solid 98.5% NaOH (0.52 g, 12.8 mmol)were dissolved in 1-propanol (10 ml) at room temperature. MTBE (20.0 m)was then added and the mixture was placed in a freezer overnight. Theprecipitated crystals were filtered and analyzed by PXRD and TGA whichshowed them to be a solvate of pantoprazole sodium and 1-propanol whichhas been denominated Form X.

Preparation of Anhydrous Pantoprazole Sodium Form XI Example 19

Pantoprazole sodium Form II (15.0 g) was dissolved in absolute methanol(75 ml). The solution was dried over 4 Å molecular sieves overnight. Thesolution was separated from the molecular sieves and the methanol wasevaporated at reduced pressure. The oily residue was triturated withacetone (50 ml) at room temperature for 4 h and then placed in arefrigerator. The solid was filtered and analyzed by PXRD and TGA whichshowed that it was an anhydrous form of pantoprazole sodium, which hasbeen denominated Form XI.

Preparation of Pantoprazole Sodium Solvate with 2-methylpropanol FormXII Example 20

Pantoprazole sodium Form II (5.0 g) was dissolved in 2-methylpropanol(10 ml) by heating at reflux. The solution was allowed to stand at roomtemperature overnight. The crystals were filtered and analyzed by PXRDand TGA which showed them to be a pantoprazole sodium solvated with2-methylpropanol which has been denominated Form XII. Drying of Form XIIat 65° C. under ambient pressure for two hours yield pantoprazole sodiumForm XIII.

Example 21

Pantoprazole sodium Form II (5.0 g) was dissolved in 2-methylpropanol (5ml) by heating at reflux. The solution was allowed to stand at roomtemperature overnight. The crystals were filtered and analyzed by PXRDand TGA which showed them to be a pantoprazole sodium Form XII.

Preparation of Pantoprazole Sodium Form XIII

Drying pantoprazole sodium 1-butanol solvate prepared as described inExample 34 or pantoprazole sodium 2-methylpropanol solvate prepared asdescribed in Example 20 at 65° C. under ambient pressure for two hoursaffords pantoprazole sodium Form XIII.

Example 22

Pantoprazole sodium Form II (5.0 g) was dissolved in acetone (10.0 ml)by heating at reflux. After a few minutes, the product was crystallizedat once. The mixture was allowed to stand at room temperature overnight.The crystals were filtered and analyzed by PXRD which showed them to benovel pantoprazole sodium Form XIII.

Example 23

Pantoprazole sodium Form II (5.0 g) was dissolved in MEK (10 ml) byheating at reflux. The solution stood at room temperature overnight,giving the crystals. The crystals were filtered and determined to bepantoprazole sodium Form XIII by PXRD.

Preparation of Pantoprazole Sodium Hydrate Form XIV Example 24

Pantoprazole sodium Form II (1.0 g) was put in a glass beaker, which wasintroduced into a bigger closed vessel (the vessel volume 125 ml),containing 20 ml of n-propanol and stored at room temperature. After 1month crystals were obtained. The solid was filtered giving PantoprazoleSodium Form XIV. The sample was dried at 50° C. under 10 mm Hg vacuumovernight giving pantoprazole sodium Form XV.

Preparation of Pantoprazole Sodium Hydrate Form XV Example 25

Pantoprazole sodium (5.0 g) was dissolved in n-propanol (5 ml) byheating at reflux. Then, the solution was cooled to room temperature andthe crystals of pantoprazole sodium Form XIV prepared as described inExample 24 were added for seeding without stirring. After 3 hours theobtained crystals were filtered giving wet Pantoprazole Sodium form XIV.The sample was dried at 50° C. under 10 mm Hg vacuum overnight givingpantoprazole sodium Form XV.

Preparation of Pantoprazole Sodium Hydrate Form XVI Example 26

A 100 ml flask was charged with toluene (50.0 ml). Pantoprazole (5.0 g,12.8 mmol) and solid 98.5% NaOH (0.575 g, 14.6 mmol) were added to thestirred solvent at room temperature followed by methanol (2 ml). Themixture was stirred until dissolution and then overnight untilprecipitation. The solid was filtered giving pantoprazole givingpantoprazole sodium Form XVI (4.65 g).

Preparation of Pantoprazole Sodium Form XVII Example 27

Amorphous Pantoprazole sodium (1 g) was slurried in MEK (5 ml) at 25° C.for 1 hr. The suspension was stirred at 750 to 1200 rpm for 24 hrs. Thecrystals were filtered and analyzed by PXRD showing a novel form ofpantoprazole sodium form XVII.

Preparation of Pantoprazole Sodium Form XVIII Example 28

Amorphous Pantoprazole sodium (4 g) was slurried in Acetone (4 ml) atroom temperature for 1 hr. The crystals were filtered, and analyzed byPXRD as wet samples and after drying at 50° C. showing a novel form ofpantoprazole sodium Form XVIII.

Preparation of Pantoprazole Sodium Form XIX Example 29

Pantoprazole sodium amorphous (4 g) was dissolved in 8 ml water andstirred for 6 hrs. at room temperature. Water was removed by evaporationunder vacuum giving a solid. The solid was then dried at 50° C.

Preparation of Pantoprazole Sodium Form XX Example 30

Amorphous pantoprazole sodium (1.0 g) was stirred with a 20:1toluene:water mixture at ambient temperature for 5 days. The resultingsolid was filtered and dried under 10 mm Hg vacuum at 50° C. overnight.

Example 31

Amorphous pantoprazole sodium (1.0 g) was stirred with a 100:1hexane:water mixture at ambient temperature for 5 days. The resultingsolid was filtered and analyzed by PXRD as wet product and after dryingin 10 mm Hg vacuum at 50° C. overnight.

Example 32

Amorphous pantoprazole sodium (1.0 g) was stirred with a 10:1hexane:water mixture at ambient temperature for 5 days. The solid wasfiltered and analyzed by PXRD as wet product and after drying in 10 mmHg vacuum at 50° C. overnight.

Example 33

Pantoprazole sodium Form II (1.0 g) was stirred with a 20:1toluene:water mixture at ambient temperature for 5 days. The solid wasfiltered and analyzed by PXRD as wet product and after drying in 10 mmHg vacuum at 50° C. overnight.

Thermal Interconversion of Pantoprazole Sodium Solvates and PolymorphicForms Example 34

Pantoprazole sodium Form II (5.0 g) was dissolved in 1-butanol (10.0 ml)by heating to reflux. The mixture was stirred overnight at ambienttemperature, giving the crystals. The crystals were filtered on filterpaper. PXRD analysis showed that the undried crystals were pantoprazolesodium Form V.

Pantoprazole sodium Form V was dried at 65° C. under ambient pressurefor two hours. PXRD analysis of the dried crystals showed that theypantoprazole sodium Form XIII.

When the pantoprazole sodium Form XIII was dried at 65° C. for anothertwo hours under ambient pressure, the product was partially amorphous.

Example 35

Pantoprazole sodium Form II (5.0 g) was dissolved in a 1:1methanol:water mixture (10 ml) at room temperature. The solution wasstirred overnight without precipitation. The solution was allowed tostand overnight in an opened flask with precipitation of the product.The crystals were filtered and allowed to stand at room temperature opento the air for a short period of time but were not otherwise dried. PXRDanalysis of the crystals revealed that they were pantoprazole sodiumForm VI.

The pantoprazole sodium Form VI was then dried at 50° C. under a 10 mmHg vacuum overnight. The resulting powder was analyzed by PXRD and foundto be amorphous.

Example 36

Pantoprazole sodium Form II (5.0 g) was dissolved in acetone (10.0 ml)by heating at reflux. The mixture was allowed to cool overnight and thecrystals were filtered the next day and analyzed by PXRD, which revealedthat they were pantoprazole sodium monohydrate Form XIII. When thecrystals were dried at 65° C. for two hours under ambient pressure theyconverted into amorphous pantoprazole sodium.

Preparation of Pantoprazole Sodium Monohydrate Example 37

Pantoprazole sodium Form II (5.0 g) was added to THF (5.0 ml) and heatedto reflux until completely dissolved. The solution was left uncoveredovernight at ambient temperature giving the crystals. The crystals werecollected on filter paper and dried at 65° C. for two hours underambient pressure. The crystals were determined by Karl Fisher analysisand PXRD to be the monohydrate.

Example 38

Pantoprazole sodium Form II (5.0 g) was dissolved in methanol (25.0 ml)at room temperature. MTBE (500 ml) was then slowly added to thesolution. The morning of the next day the crystals were filtered anddried at 65° C. for two hours under ambient pressure. The crystals weredetermined by Karl Fisher analysis and PXRD to be the monohydrate.

Example 39

Pantoprazole sodium Form II (5.0 g) was dissolved in 2-propanol (50.0ml) at room temperature. Cyclohexane (20 ml) was then slowly added tothe solution. Pantoprazole sodium initially was separated as an oil, butafter the mixture was allowed to stand at room temperature in an openedflask for a week the oil had transformed to crystals. The crystals werefiltered and dried at 65° C. for two hours under ambient pressure. Thecrystals were determined by Karl Fisher analysis and PXRD to be themonohydrate.

Example 40

Pantoprazole sodium Form II (5.0 g) was dissolved in acetonitrile (25.0ml) at room temperature. Toluene (250 ml) was then slowly added to thesolution. Pantoprazole sodium initially was separated as an oil, butafter the mixture was allowed to stand at room temperature in an openflask for two days the oil had transformed to crystals. The crystalswere filtered and dried at 65° C. for two hours under ambient pressure.The crystals were determined by Karl Fisher analysis and PXRD to be themonohydrate.

Example 41

Pantoprazole sodium Form II (5.0 g) was dissolved in acetonitrile (25.0ml) at room temperature. MTBE (250 ml) was then slowly added to thesolution. The mixture was allowed to stand for two days, giving thecrystals. The crystals were filtered and dried at 65° C. for two hoursunder ambient pressure. The crystals were determined by Karl Fisheranalysis and PXRD to be the monohydrate.

Example 42

Pantoprazole sodium Form II (5.0 g) was dissolved in 1-propanol (5.0 ml)by heating at reflux. The mixture was allowed to stand overnight atambient temperature and in the morning, the crystals were filtered anddried at 50° C. under 10 mm Hg vacuum overnight. The crystals weredetermined by Karl Fisher analysis and PXRD to be the monohydrate.

Example 43

Pantoprazole sodium Form II (5.0 g) was added to dimethylcarbonate (5.0ml) at room temperature. The suspension was stirred at room temperaturefor 24 h. The crystals were separated from the dimethylcarbonate byfiltration and were dried at 50° C. under 10 mm Hg vacuum overnight. Thecrystals were determined by Karl Fisher analysis and PXRD to be themonohydrate.

Example 44

Pantoprazole (5.0 g, 12.8 mmol) and solid 98.5% NaOH (0.52 g, 12.8 mmol)was added to 1-propanol (10 ml) and stirred at room temperature untilthe NaOH completely dissolved. MTBE (20.0 ml) was then slowly added.Upon completing the addition, the solution was placed in a freezerovernight, giving the crystals. The crystals were filtered and dried at50° C. under 10 mm Hg vacuum overnight. The crystals were determined byKarl Fisher analysis and PXRD to be the monohydrate.

Example 45

Amorphous pantoprazole sodium (1.6 g) was added to acetone (3.2 ml) atroom temperature. The suspension was stirred at room temperature for 2h. The solid was filtered and dried at 50° C. under 10 mm Hg vacuumovernight. The crystals were determined by Karl Fisher analysis and PXRDto be the monohydrate.

Example 46

Pantoprazole sodium sesquihydrate (5.0 g) was added to dimethylcarbonate(50 ml). The suspension was stirred for three days at room temperature.The crystals were filtered and dried at 50° C. under 10 mm Hg vacuumovernight. The crystals were determined by Karl Fisher analysis and PXRDto be the monohydrate.

Preparation of Pantoprazole Sodium Sesquihydrate Example 47

Pantoprazole sodium Form II (5.0 g) was dissolved in 2-propanol (5.0 ml)by heating at reflux. After standing overnight at room temperature themixture remained a clear solution. The solvent was allowed to evaporatewhile the mixture was allowed to stand uncovered at room temperature foranother night. The crystals were filtered and dried at 65° C. underambient pressure for two hours. The crystals were determined by KarlFisher analysis and PXRD to be the sesquihydrate.

Example 48

Pantoprazole sodium Form II (5.0 g) was dissolved in THF (10.0 ml) byheating at reflux. The solution was stirred overnight in a closed flaskat ambient temperature. No crystals had formed by the next day, so thesolution was allowed to stand another night in an opened flask. Thistime, crystals formed in the flask. The crystals were filtered on filterpaper and dried at 65° C. under ambient pressure for two hours. Thecrystals were determined by Karl Fisher analysis and PXRD to be thesesquihydrate.

Example 49

Pantoprazole sodium Form II (5.0 g) was dissolved in acetonitrile (5.0ml) by heating at reflux. The solution was stirred overnight in a closedflask at ambient temperature giving the crystals. The crystals werefiltered and dried at 65° C. under ambient pressure for two hours. Thecrystals were determined by Karl Fisher analysis and PXRD to be thesesquihydrate.

Example 50

Pantoprazole sodium Form II (5.0 g) was dissolved in ethanol (5.0 ml) byheating at reflux. The solution was stirred overnight in a closed flaskat ambient temperature. No crystals formed. Heptane (5.0 ml) was addedto the solution and the mixture was again stirred overnight. Again, nocrystals formed. Finally, the flask was opened and the solution was leftexposed to the atmosphere for another night. The precipitated crystalswere filtered and dried at 65° C. under ambient pressure for two hours.The crystals were determined by Karl Fisher analysis and PXRD to be thesesquihydrate.

Example 51

Pantoprazole sodium Form II (5.0 g) was dissolved in water (5.0 ml) byheating at reflux. The solution was stirred overnight in a closed flaskat ambient temperature. No crystals formed. The flask was opened and thesolution was left exposed to the atmosphere for another night. Theprecipitated crystals were filtered and dried at 50° C. under 10 mm Hgvacuum overnight. The crystals were determined by Karl Fisher analysisand PXRD to be the sesquihydrate.

Example 52

Pantoprazole sodium Form II (5.0 g) was dissolved in a 5:4 mixture ofsec-butanol:dichloromethane (90 ml) at room temperature. The solutionwas stirred overnight in a closed flask without a change in appearance.The flask was opened and the solution was left exposed to the atmospherefor another night. The crystals were filtered and dried at 50° C. under10 mm Hg vacuum overnight. The crystals were determined by Karl Fisheranalysis and PXRD to be the sesquihydrate.

Example 53

Pantoprazole sodium Form II (5.0 g) was dissolved in ethyl acetate (50.0ml) by heating at reflux. The solution was stirred overnight in a closedflask at ambient temperature. No crystals formed. The solution was thenconcentrated to about 5 ml. The concentrated solution was left in anuncovered flask for another night, giving the crystals The crystals werefiltered and dried at 65° C. under ambient pressure. The crystals weredetermined by Karl Fisher analysis and PXRD to be the sesquihydrate.

Example 54

Pantoprazole sodium Form II (5.0 g) was added to ethyl acetate (50.0 ml)at room temperature. The suspension was stirred at room temperature for24 h. The crystals were filtered and dried at 50° C. under 10 mm Hgvacuum overnight. The crystals were determined by Karl Fisher analysisand PXRD to be the sesquihydrate.

Example 55

Pantoprazole sodium Form II (5.0 g) was added to dichloromethane (50.0ml) at room temperature. The heterogeneous mixture was stirred at roomtemperature for 24 h. The crystals were filtered and dried at 50° C.under 10 mm Hg vacuum overnight. The crystals were determined by KarlFisher analysis and PXRD to be the sesquihydrate.

Example 56

Pantoprazole sodium Form II (5.0 g) was added to water (5.0 ml) at roomtemperature. The suspension was stirred at room temperature for 24 h.The crystals were filtered and dried at 50° C. under 10 mm Hg vacuumovernight. The crystals were determined by Karl Fisher analysis and PXRDto be the sesquihydrate.

Example 57

Pantoprazole sodium Form I (5.0 g) was added to dimethylcarbonate (50.0ml) at room temperature. The suspension was stirred at room temperaturefor 24 h. The crystals were filtered and dried at 50° C. under 10 mm Hgvacuum overnight. The crystals were determined by Karl Fisher analysisand PXRD to be the sesquihydrate.

Example 58

Pantoprazole sodium Form II (5.0 g) and water (0.4 ml) were subjected torotary mixing in a rotary evaporator without vacuum at room temperaturefor two hours. The crystals were determined by Karl Fisher analysis andPXRD to be the sesquihydrate.

Example 59

Pantoprazole sodium Form II (5.0 g) and a 1:1 mixture of2-propanol:water (0.4 ml) were subjected to rotary mixing in a rotaryevaporator without vacuum at room temperature for two hours. Thecrystals were determined by Karl Fisher analysis and PXRD to be thesesquihydrate.

Example 60

Pantoprazole sodium Form II (1.0 g) was placed in glass which was putinto a 125 ml closed vessel containing 20 ml of ethyl acetate. Thepantoprazole sodium was exposed to the ethyl acetate vapors for twoweeks at ambient temperature giving the crystals which were analyzed byKarl Fisher analysis technique and PXRD and found be the sesquihydrate.

Example 61

Pantoprazole (5.0 g, 12.8 mmol) and solid 98.5% NaOH (0.52 g, 12.8 mmol)were added to methanol (10 ml) and stirred at room temperature until theNaOH was completely dissolved. The mixture was stirred overnight in aclosed flask. No crystals formed. The flask was opened and the solutionwas stirred overnight. No crystals had formed by the next day. MTBE (50ml) was added to the mixture. The mixture was stirred for two hours,giving the crystals. The crystals were isolated by filtration and driedat 50° C. under 10 mm Hg vacuum overnight. The dried crystals weredetermined by Karl Fisher analysis to be the sesquihydrate.

Example 62

Pantoprazole (5.0 g, 12.8 mmol) and solid 98.5% NaOH (0.52 g, 12.8 mmol)were added to ethanol. (10 ml) and stirred at room temperature until theNaOH was completely dissolved. The mixture was stirred overnight in aclosed flask. No crystals formed. The flask was opened to the air andthe solution was stirred overnight. No crystals had formed by the nextday. MTBE (50 ml) was added to the mixture. The mixture was stirred fortwo hours, giving the crystals. The crystals were isolated by filtrationand dried at 50° C. under 10 mm Hg vacuum overnight. The dried crystalswere determined by Karl Fisher analysis to be the sesquihydrate.

Example 63

Pantoprazole (5.0 g, 12.8 mmol) and solid 98.5% NaOH (0.52 g, 12.8 mmol)were added to 2-propanol (10 ml) and stirred at room temperature untilthe NaOH was completely dissolved. The mixture was stirred overnight ina closed flask. No crystals formed. MTBE (20 ml) was added to themixture. The mixture was stirred overnight, but no crystals formed. Themixture was then stirred overnight in an opened flask, giving thecrystals. The crystals were isolated by filtration and dried at 50° C.under 10 mm Hg vacuum overnight. The dried crystals were determined byKarl Fisher analysis to be the sesquihydrate.

Example 64

Pantoprazole (5.0 g, 12.8 mmol) and solid 98.5% NaOH (0.52 g, 12.8 mmol)were added to sec-butanol (10 ml) and stirred at room temperature untilthe NaOH was completely dissolved. The mixture was stirred overnight ina closed flask. No crystals formed. MTBE (20 ml) was added to themixture. The mixture was then stirred overnight in an open flask, givingthe crystals. The crystals were isolated by filtration and dried at 50°C. under 10 mm Hg vacuum overnight. The dried crystals were determinedby Karl Fisher analysis to be the sesquihydrate.

Having thus described the invention with respect to certain preferredembodiments and further illustrated it with examples, those skilled inthe art may come to appreciate substitutions and equivalents that albeitnot expressly described are taught and inspired by this invention.Whereas such substitutions and equivalents do not depart from the spiritof the invention they are within its scope which is defined by theclaims that follow.

1-133. (canceled)
 134. A process for preparing pantoprazole sodiumsesquihydrate: a) dissolving pantoprazole and a source of sodium ions ina diluent selected from the group consisting of 2-propanol,tetrahydrofuran, acetonitrile, methanol, ethanol, water, mixtures ofsec-butanol and dichloromethane, and ethyl acetate to form a solution,and b) crystallizing pantoprazole sodium sesquihydrate from thesolution, and c) isolating the crystals from the diluent.
 135. Theprocess of claim 134 wherein the diluent is selected from the groupconsisting of methanol and ethanol.
 136. The process of claim 134wherein the source of sodium ions is a mixture of sodium hydroxide andwater.
 137. (canceled)
 138. A process for preparing pantoprazole sodiumsesquihydrate comprising: a) forming a heterogeneous mixture by mixingpantoprazole sodium and a diluent selected from the group consisting ofethyl acetate, dichloromethane, water, dimethylcarbonate and 2-propanoland mixtures thereof, and b) recovering pantoprazole sodiumsesquihydrate from the heterogeneous mixture.
 139. The process of claim138 wherein the diluent is selected from the group consisting of waterand mixtures of water and 2-propanol.
 140. The process of claim 138wherein the diluent is selected from the group consisting of ethylacetate, dichloromethane, water and dimethylcarbonate.
 141. The processof claim 139 wherein the diluent and pantoprazole sodium are present ina weight ratio of about 1:1.
 142. The process of claim 140 wherein thediluent and pantoprazole sodium are present in a weight ratio of about1:1 or greater.
 143. The process of claim 138 wherein the pantoprazolesodium of step a) is crystalline pantoprazole sodium Form II.
 144. Theprocess of claim 134 wherein the solution is formed by dissolving thepantoprazole in the diluent, followed by adding the source of sodiumions, wherein the source of sodium ions is in solution in the diluent.145. A process for preparing pantoprazole sodium sesquihydratecomprising: a) dissolving pantoprazole sodium Form II in a diluentselected from the group consisting of 2-propanol, tetrahydrofuran,acetonitrile, ethanol, water, mixtures of sec-butanol anddichloromethane, and ethyl acetate to form a solution, and b)crystallizing pantoprazole sodium sesquihydrate from the solution.